ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

Transcription

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2 PrEP Rona Vail, MD, AAHIVS HIV Lead Clinician Callen-Lorde Community Health Center

3 Learning Objectives Upon completion of this presentation, learners should be better able to: 1. Explain the rationale behind PrEP 2. Review PrEP guidelines and studies, along with their implications for practice 3. Discuss challenges and controversies in PrEP therapy

4 Faculty and Planning Committee Disclosures Please consult your program book. No financial disclosures Off-Label Disclosure The following off-label/investigational uses will be discussed in this presentation: PrEP therapies currently in development

5 How many individuals have you prescribed PrEP for? 1. 0 I am not a prescriber 2. 0 I am a prescriber >20

6 Overview PrEP questions: Who needs PrEP? Is PrEP effective? Is PrEP safe? Does PrEP lead to increased risk behaviors/sti s? What is in the PrEP pipeline?

7 Definitions HIV PEP (Post Exposure Prophylaxis) The use of antiviral medication, initiated AFTER exposure, to prevent HIV infection- short term Tenofovir/Emtricitabine (Truvada) plus raltegravir (Isentress) or dolutegravir (Tivicay) HIV PrEP (Pre-exposure prophylaxis) Use of antiviral medication in an HIV negative person, initiated BEFORE exposure, to prevent HIV infection Tenofovir/emtricitabine (TDF/FTC) = Truvada

8 Jamal 24 yo AA gay male; initially seen 5 months ago when he presented for PEP after an encounter of condomless anal sex with partner of unknown HIV status after a night of heavy drinking Comes in today presenting again for PEP, due to another condomless encounter he had last night with someone of unknown HIV status. Has been mostly consistent with condoms but sometimes I just get caught up in the moment

9 What do you recommend regarding PrEP? 1. I would recommend he start PrEP today 2. I would recommend PEP, but I would not recommend PrEP at this point as he is not high risk. 3. I would recommend PEP and then immediate transition to PrEP if he agrees to PrEP. 4. I would recommend PEP and then refer him for counseling to reduce his risk prior to considering PrEP.

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11 CDC: HIV Incidence down 18% from 2008 to 2014, BUT New HIV infections remained stable or decreased in many MSM, but rose in MSM aged ,000 10,000 8,000 6,000 4,000 2, Further breakdown of this category: the rise is occurring in yo CDC Feb 2018 Rates have not decreased in Black MSM, and have risen in Latino MSM 66% of new infections in heterosexuals are AA Singh S, et al. CROI Seattle, WA. Oral Abstract # 30 February 14, 2017.

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13 Shifting Prevention Strategies 1980 s : Education/behavior change/condoms/clean needles Now: Education/behavior change/condoms/clean needles, but also: 1. TasP (Treatment as Prevention) 2. HIV Testing and linkage to care 3. PEP 4. PrEP

14 FDA Approval In July 16, 2012, FDA approved the use of tenofovir (300mg) + emtricitabine (200 mg) (TDF/FTC or Truvada ) for HIV PrEP in adults who are at high risk for becoming HIV-infected àdosage: One tablet once daily taken orally with or without food

15 PrEP guidelines

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17 Provider-Patient Barriers Surveyed users of gay pick up website (n=1394) 42% are not comfortable discussing sex with PCP >80% have not discussed PrEP with PCP 75% don t think their provider would prescribe PrEP 48% had condomless anal sex with 3 or more partners in 3 months Communication about risk behaviors and about PrEP in primary care is KEY Krakow, et.al IAS 2015, Vancouver. Abstract TUPEC506

18 Is PrEPEffective?

19 iprex Trial Phase 3, double-blind, randomized, placebo-controlled, 11 sites in 6 countries, n=2499 Adult HIV(-) MSM or transgender women in the US, Peru, Ecuador, Brazil, Thailand, South Africa, 18 yo or older, at high risk of HIV acquisition Two study arms: - TDF/FTC (300mg/200mg) orally once daily - Placebo Primary Outcome: Prevention of HIV Outcome: 44% reduction in HIV acquisition (p <0.002) Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587-2

20 iprex: HIV by Group and Drug Detection Group Drug Detection HIV Infections Incidence Density Placebo No FTC/TDF No Yes Relative Rate Reduction by use of FTC/TDF 91% Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587-2

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22 How much adherence is enough?

23 iprex Open-Label Extension (OLE): HIV Incidence and Risk Reduction by Detectable Drug No new HIV infections in those who took 4 or more tabs per week Grant RM, et al. 20 th IAC. Melbourne, Abstract TUAC0105LB. Grant RM, et al. Lancet Infect Dis. 2014;July 22, [Epub ahead of print].

24 Drug concentration varies in different mucosal tissues PrEP does not reach the same levels in vagina and cervix Estimated that women need to take 6-7 doses/wk for efficacy Patterson KB, et al. Sci Transl Med. 2011;3:112re4.

25 Role of the vaginal microbiome Healthy vaginal microbiome (lactobaccillus predominant) is important to HIV prevention Vaginal dysbiosis- key factor in vaginal inflammation, epitheilial barrier integrity and HIV acquisition Dysbiotic bacteria can metabolize TDF and dapivirine CAPRISA 004 Tenofovir gel Overall 39% efficacy Lactobacillus dominant 61% efficacy Dysbiotic 18% efficacy Effect of dysbiosis on oral drug metabolism? Nicole Klatt, plenary CROI 2018

26 Adherence may need to be significantly higher in IDU The Bangkok Tenofovir Study DOT participants 70% decrease in HIV Higher adherence levels to get same protection as rectal exposure Choopanya K, et al. Lancet. 2013;381:

27 Time to protection Time to maximum intracellular concentrations (healthy volunteers): Rectal tissue ~7 days Blood ~20 days Cervico-vaginal tissue ~20 days Penile tissue??? Neo-vagina??? US Public Health Services. Preexposure Prophylaxis For The Prevention Of HIV Infection In The United States,

28 Infection with Multidrug Resistant HIV Despite Adherence to PrEP- 2 case reports Case report 1: 43 yo MSM, adherence verified by mass spectography and dried blood spot. mutations: 41L, 67G, 69D, 70R, 184V, 215E, 181C, 10I, 51Y, 92Q Case report 2: MSM 20 s, hair samples showed adherence. mutations: K65R, M184V, K103S, E138Q, Y188L PrEP adherence, but exposed to virus from partners with extensive mutations Knox, D. et.al. CROI 2016, Boston, MA. #169aLB Grossman, H, et.al. HIV Research for Prevention HIVR4P 2016). Chicago, IL. OA03.06LB

29 HIV Acquisition despite adherence: case report 50 yo MSM, reported excellent adherence on PrEP (Adequate TDF levels at 6 and 8 mos) 8 months after starting PrEP Fever and dysuria HIV Ab+, HIV Ag and HIV RNA neg, HIV DNA neg PrEP stopped, HIV RNA developed 3 weeks later No mutations on sequencing During PrEP use anal sex partners per month, 2 episodes anal GC, 1 episode anal CT Drug use during sex (cocaine, amphetamine, GHB/GBL, mephedrone, ketamine) Hoornenborg E, et al. CROI Seattle, WA. Poster #953

30 PrEP effectiveness takeaways: Perfect adherence to PrEP is an excellent but not perfect predictor of PrEP success Site of exposure dictates degree of adherence required/degree of forgiveness of missed doses Tenofovir resistance in HIV+ is rare, but when present, can overcome HIV protection from PrEP with TDF/FTC

31 Is PrEP safe?

32 iprex Results: Safety TDF/FTC was well tolerated GI-Nausea (2% vs <1%) and weight loss >5% (2% vs 1%) No differences in severe (grade 3) or life-threatening (grade 4) laboratory abnormalities Renal safety No cases of RTA 10 subjects (7 tdf/ftc, 3 placebo) discontinued for creatinine elevation, all normalized 9 reinitiated treatment Bone safety (BMD substudy) Small net decrease in spine and total hip BMD (<1%) vs placebo at 24 weeks, stable at 96 weeks BMD recovered after discontinuation of drug. No difference in fracture rates. Grant RM, Lama JR, Anderson PL, et al.. N Engl J Med2010;363: Mulligan, K. et. al, Clin Infect Dis. 2015;61(4):

33 iprex OLE : Probability of egfr Decreasing to <70 ml/min Within a Year Gandhi M, et al. 23 rd CROI. Boston, Abstract 866.

34 Jamal 24 yo AA gay male; initially seen 5 months ago when he presented for PEP after an encounter of condomless anal sex with a partner of unknown HIV status after a night of heavy drinking Comes in today presenting again for PEP, due to another condomless encounter he had last night with someone of unknown HIV status. He states he has been mostly consistent with condoms but sometimes I just get caught up in the moment

35 What do you recommend re PrEP? 1. I would recommend he start PrEP today 2. I would recommend PEP, but I would not recommend PrEP at this point as he is not high risk. 3. I would recommend PEP and then immediate transition to PrEP if he agrees to PrEP. 4. I would recommend PEP and then refer him for counseling to reduce his risk prior to considering PrEP.

36 James James is a 42 yo gay man who comes in asking for PrEP. He is tired of feeling anxious that he will get infected every time he has sex. He states that he is tired of using condoms, and wants to experience the intimacy that comes from not using them.

37 Would you prescribe PrEP for James? 1. Yes, I would prescribe PrEP. 2. No, I would not prescribe PrEP since he does not meet the guidelines for high risk 3. I don t know what I would do.

38 James Condom fatigue Intimacy Anxiety about becoming infected Control for receptive partners

39 PrEP is a demand-driven intervention, meaning that the indication for PrEP is that someone asks for it. This implies that people are good at determining their own risk and that overly tight criteria for offering PrEP are unnecessary because people will self-regulate in terms of use and uptake. Robert Grant of UCSF

40 James, 6 months later James states that he is doing well with PrEP, has a system so is not missing doses. He has no symptoms today and is feeling well On routine screening he is found to have anal chlamydia

41 Does PrEP increase risk behavior/increase STIs?

42 100 iprex Study: Risk compensation Condomless Receptive Anal Intercourse Overall Patient Population Emtricitabine/tenofovir DF Placebo Patients Who Believed They Were Receiving FTC/TDF 100 Emtricitabine/tenofovir DF Placebo Patients (%) P=0.30 Patients (%) P= Weeks PROUD study, IPERGAY study: no risk compensation Weeks Marcus JL, et al. PLoS One ;8:e81997.

43 STI Data from Community-Based PrEP programs NYC SPARK (n=280) 1 The Demo Project (n=557) 2 STIs pre-prep 21% >25% STIs on PrEP 13-21% quarterly 18-25% quarterly STIs that CDC guidelines* would have missed (asymptomatic at 3M and 9M) 77% at 3M; 68% at 9M 34% GC; 40% CT; 20% syphilis Extragenital STIs % quarterly 83% GC; 76% CT *Current CDC guidelines recommend STI screening q6mo and asking about symptoms quarterly NYC SPARK STI diagnoses by time point 1 Not screening extra-genital sites and only following the CDC s current STI screening guidelines would miss or delay many STI diagnoses 25% 15% 5% Symptomatic Routine 1. Golub S, et al. CROI Boston, MA. # Cohen S, et al. CROI Boston, MA #870-5% Pre-PrEP 3M 6M 9M 12M

44 Screening for STI s on PrEP CDC 2014 PrEP guidelines Every 3 months: STI symptom assessment Every 6 months: test for bacterial STI s CDC 2017 PrEP guidelines update: Every 3 to 6 months, test for bacterial STI s My guideline: Test for bacterial STI s every 3 months, can consider every 6 month screening in individuals at lower STI risk CDC: Preexposure Prophylaxis for the Prevention of HIV Infection in the United States 2014 Clinical Practice Guideline CDC: Preexposure Prophylaxis for the Prevention of HIV Infection in the United State 2017 Update Clinical Practice Guideline

45 PrEP plus Screening Could Decrease STI rates: a modeling study Increasing PrEP coverage increases screening, which increases diagnosis of asymptomatic STIs At 40% PrEP coverage and 40% risk compensation, 42% of GC and 40% of CT infections would be avoided in the next 10 years If STI screening is done quarterly instead of biannually: 50% further reduction in STI rates Even 80% risk compensation with PrEP use would lead to a decrease in STI rates Jenness SM, et al. CROI Seattle, WA. Poster #1034

46 James, one year later James comes in for his routine follow up. He states PrEP is going well, and other than a couple of missed doses he has been perfect in his adherence to medication However, he finds that he is not that sexually active right now, and has heard that the medication can be taken intermittently. He wants to know if he can take PrEP only when he plans to have sex, instead of taking it every day if he doesn t really need it

47 IPERGAY Dosing Schedule: 1 Sexual Event 2 tablets (TVD + placebo) 2-24 hours before sex Sexual Event 1 tablet (TVD or placebo) 24 hours later 1 tablet (TVD or placebo) 48 hours later Monday Tuesday Wednesday Thursday Friday Saturday Sunday First evidence that an event-driven regimen was effective among high-risk MSM with frequent sex (median of 10 sex acts per month and 8 partners every two months). Men were taking PrEP an average of three to four days per week. CDC: researchers do not yet know if this regimen will work among MSM who have sex less frequently or among other populations at high risk for HIV infection. CDC: urges people at substantial risk for HIV infection and their health care providers to continue to follow current CDC guidelines Molina J, et al. CROI 2015; Seattle, WA. #23LB 47

48 Planning for the Pre-Event Dose: Social Network Survey How far ahead planned? Last anal sex planned N= 1013 US MSM Unplanned Planned Minutes Hours 1-3 days >3 days 59% reported last sex was unplanned or planned only minutes in advance Volk J, et al. JAIDS 2012;61(1):

49 Milagros Milagros is a 26 yo transgender female who recently discovered that her boyfriend is HIV+ by finding a pill bottle and looking up the medication on Google She is anxious about confronting him, but also worried about getting HIV. She wants to know what she can do to stay safe, since she feels she can not ask him now to start using condoms when they had not been prior

50 PrEP/HIV in transgender populations Which of the following statements is FALSE? 1. Transgender women have higher rates of HIV infection than MSM 2. PrEP was as effective in Trans women as in MSM in the iprex study 3. There is less awareness of PrEP in the trans community than in the MSM community 4. Concerns about interactions with hormones lead some transwomen to prioritize hormones over PrEP

51 HIV/PrEP in trans populations Transgender women- ~21.7 % HIV prevalence times higher than the general population Multilevel HIV vulnerabilities-stigma, discrimination, violence victimization, limited access to housing, lack of employment opportunities that lead to higher rates of sex work PrEP uptake and awareness among TW has been low. Adherence of TW in iprex was 18%, and not correlated to risk. Lack of trans-inclusive marketing. Concerns about interactions with hormones lead some women to prioritize hormones over PrEP (and ART) C Poteat. HIV in Transgender Populations: Charted and Uncharted Waters Conference on Retroviruses and Opportunistic Infections, Boston, February 22-25, Abstract 79. Deutsch, et al, HIV pre-exposure prophylaxis in transgender women: A subgroup analysis of the iprex trial. Lancet Vol 2, no 12, e , Dec 2015

52 HIV/STI Risk for Trans Men Even less known about TGM Prevalence of HIV 0-3% Prevalence of STIs 6-47% Sexual partners: - Females 30.4% - Males only 30.4% - Both females and males 34.8% Both anal/vaginal sex Low rates of condom use (30%) (Herbst, 2007; Conare, 1997; Kenagy, 2002; Reisner, 2010 ; Rowniak, 2011; Sevelius 2009 Green, Medicine 94(41) 2015 Slide courtesy of Dr A Radix

53 We need to improve outreach, and address social and structural barriers to PrEP CDC

54 The PrEP Pipeline

55 Summary PrEP is now part of a menu of evidence-based interventions to prevent HIV transmission. Awareness/interest/demand has risen dramatically in the past couple of years- we need more providers who are comfortable with prescribing PrEP We need to do better in reaching out to younger MSM, communities of color, trans men and women

56 Thank You!